The broad, long-term objective of this proposal is to understand the role of the tissue factor-thrombin-PAR-1 pathway in viral infections. This is an understudied area. Viral infections are detected by various intracellular receptors, including toll-like receptor (TLR) 3. The clotting system is activated during viral infections as part of the host innate immune response. Coagulation proteases, such as thrombin, in the clotting system activated cells by cleavage of PARs, including PAR-1. In humans PAR-1 is the major thrombin receptor on platelets and is the target of the new antiplatelet drug vorapaxar. Mice do not express PAR-1 on their platelets and allow us to investigate the role of PAR-1 in cells other than platelets. We found that the tissue factor-thrombin-PAR-1 pathway protected mice from infection with coxsackievirus B3 (CVB3) and influenza A virus (IAV). We found that PAR-1 activation enhanced TLR3-dependent IFN? expression. A type I interferon response plays a central role in fighting viral infections. The current proposal will extend our exciting discovery and determine the role of PAR-1 in different cell types in CVB3-induced myocarditis and IAV infection of the lung using a variety of transgenic mouse lines. Our proposal has 2 specific aims. Specific Aim 1: Determine the role of PAR-1 expressed on different cell types in the host response to CVB3-induced myocarditis. General hypothesis: PAR- 1 contributes to the antiviral response to CVB3 infection of the heart by enhancing IFN? expression and by inhibiting viral replication. Specific Aim 2: Determine the role of PAR-1 expressed on different cell types in the host response to influenza A. General hypothesis: PAR-1 expression by EC contributes to the maintenance of vascular integrity and PAR-1 on hematopoietic cells regulates the antiviral response in the lung after IAV infection. Viral infections cause considerable morbidity and mortality worldwide. Our studies are significant because they may elucidate new pathways in the host defense system that are used to combat viral infections.